Randomized Withdrawal study design is
not new and has been practically used in many drug trials and in NDA or BLA
applications. It may be called 'randomized discontinuation trial' or 'randomized discontinuation design' in some literature. Randomized Withdrawal study design is especially popular in CNS and
neurology areas.

“In a randomized withdrawal trial,
subjects receiving a testtreatment for
a specified time are randomly assigned to continued treatment with the test
treatment or to placebo (i.e., withdrawal of active therapy).Subjects for such a trial could be derived
from an organized open single-arm study, from an existing clinical cohort (but
usually with a protocol-specified "wash-in" phase to establish the
initial on-therapy baseline), from the active arm of a controlled trial, or
from one or both arms ofan active
control trial.Any difference that emerges
between the group receiving continued treatment and the group randomized to placebo
would demonstrate the effect of the active treatment.The pre-randomization observation period on
treatment can be of any length; this approach can therefore be used to study
long-term persistence of effectiveness when long-term placebo treatment would
not be acceptable.The post-withdrawal
observation period could be of fixed duration or could use early escape or time to event (e.g.,
relapseof depression) approaches.As with the early escape design, careful
attention should be paid to procedures for monitoring patients and assessing
study endpoints to ensure that patients failing on an assigned treatment are identified rapidly.

“The advantages of this study design are that individuals receiving
the experimental intervention continue to do so only if they respond, whereas
individuals receiving the placebo do so only until their symptoms return.
Disadvantages include carryover effects, difficulties assessing whether the
underlying disease process is still active, and long lag times to adverse
events if the disease is in remission. This design is more appropriate in phase
I and II trials involving healthy volunteers because it is less likely that
effective treatments are being withdrawn from those who need it. In some
studies, however, measurement of the placebo effect is essential (e.g., studies
of drugs for the treatment of depression), and such studies might require the
use of a randomized withdrawal design. In those cases, voluntary, informed
consent is essential, as is the provision of care during the withdrawal period.”

Additional advantage of this design is to study the long-term efficacy or safety (withdrawal effect) and additional disadvantage is the longer overall study period (additional period is needed to identify responders).

Some of the practical
cases of using the Randomized Withdrawal Design in clinical trial are:

Flibanserin (a so-called Female
Viagra drug) for the treatment of hypoactive
sexual desire disorder (PSDD) in premenopausal women. One of the pivotal
trials began
with a 24-week open label phase, which then enrolled only “responders” into the
randomized withdrawal phase

IGIV-C for the
treatment of chronicinflammatory
demyelinating polyradiculoneuropathy(ICE study): the trial had two randomization. The second randomization was only for
responders (to IGIV-C or Placebo) from initial (the first) randomized period. In extension period, the randomized
withdrawal design was employed. The responders were re-randomized to IGIV-C or
Placebo to study the long-term efficacy by comparing the relapse rates and the
time to relapse. Notice that the responders from Placebo group in initial (first) randomized period were also
included in the randomized withdrawal period. This is purely for maintaining
the blinding.